In 1928, while Szent-Györgyi was still at Cambridge, the
Hungarian minister of education, Count Kuno Klebelsberg,
invited him to return to Hungary to chair the medical
chemistry department at the University of Szeged.
Klebelsberg wanted to rebuild Hungarian scientific
institutions, and had obtained Rockefeller Foundation (RF)
support for expanding the programs at Szeged. Though
Szent-Györgyi loved Cambridge, there was little chance of
advancement there, so he accepted the offer, taking up his
new position in January 1931.

Szent-Györgyi's new responsibilities included teaching and
administration as well as research. He soon established a
reputation for fascinating lectures and an informal
leadership style. More traditional faculty were sometimes
startled or affronted by Szent-Györgyi's behavior: dining
or playing sports with his students, riding his bicycle to
visit colleagues (as was common at Cambridge)--but the
students loved him for his free and spontaneous approach to
education.

After only six months Szent-Györgyi had established a small
but important research center with over a dozen different
projects in progress. Within a year he had initiated
Hungary's first degree program in biochemistry (which he
distinguished from the "medical chemistry" taught in
medical schools), and had eight RF fellows on his faculty.
He was also chairman of the Natural Science Research
Council in Szeged, which administered the $200,000 RF
grant. His dealings with the RF during the next several
years set what became a lifelong pattern with regard to
funding agencies: initial enthusiasm, followed by
frustration and disillusionment (on both sides) as
Szent-Györgyi made extravagant claims and requested additional
funds, but balked at justifying the expenses with detailed
research plans and budgets.

In the fall of 1931, an American post-doctoral fellow,
Joseph Svirbely, joined Szent-Györgyi's research team.
Svirbely had been working with C. G. King at the University
of Pittsburgh, trying to isolate vitamin C. Szent-Györgyi
gave him the remains of the hexuronic acid he had isolated
at the Mayo Clinic and asked him to test it, using guinea
pigs with induced scurvy. Repeated trials proved that
"hexuronic acid" was, in fact, vitamin C. (Szent-Györgyi
had suspected this, but had put the project aside rather
than take up the messy, expensive, and labor intensive
animal studies required.) King, meanwhile, had also been
close to reaching a similar conclusion. Svirbely wrote to
his former mentor in March 1932, telling King what he had
found at the Szeged laboratory, adding that he and
Szent-Györgyi were submitting a report to Nature.
On April 1,
1932, Science published King's announcement
that he had
discovered vitamin C, which was identical to hexuronic
acid. King cited Szent-Györgyi's earlier work on hexuronic
acid but gave him no credit for vitamin C. The discovery story
was picked up quickly by the American
press. Astonished and dismayed, Szent-Györgyi and Svirbely
sent off their own report to Nature,
challenging King's
priority in the discovery. A bitter controversy ensued.
King, as was well-known, had been working on the problem
for over five years; he had many supporters, who were ready
to vilify Szent-Györgyi as a plagiarist. Yet European and
British scientists also knew of Szent-Györgyi's long
history with this anti-oxidant substance and accepted his
claim.

Apart from the question of priority, Szent-Györgyi had a
more immediate problem: he could not repeat the experiments
with vitamin C because he had used up the last of his
supply. He had no large supply of adrenal glands on hand
from which to extract more, and attempts with various
fruits and vegetables failed as well. In the fall of 1932
it occurred to him to test paprika peppers for vitamin C
content. Paprika proved to be a very rich source of vitamin
C, and supply was no problem--Szeged was the paprika capital
of Hungary. Szent-Györgyi immediately mobilized his staff
for the large-scale extraction of vitamin C from peppers.
Within a week, they had produced over three pounds of the
pure crystalline substance. Rather than patent the process
or the product, Szent-Györgyi sent batches to all
researchers working on vitamin C or related problems
(including Norman Haworth at Birmingham, who established
its chemical nature, and then, with Szent-Györgyi, re-named
it "a-scorbic" acid, since it prevented scorbutus, i.e.,
scurvy). Szent-Györgyi also sent a supply to the Health
Organization of the League of Nations, to distribute in
areas where scurvy was still prevalent (e.g., Norway).

Szent-Györgyi spent the next several years "preaching
vitamin C" (as he put it) all over Europe, suggesting that
it might be valuable as a preventive or cure for the common
cold and other illnesses. He attempted to interest some of
the British biochemists in running some clinical trials,
but they considered the idea crankish and refused to
consider it. Vitamin C proved disappointing as a miracle
cure, however, and Szent-Györgyi eventually got back to his
basic research in other areas.

In the meantime, building on his earlier work in the
biochemistry of plant respiration, Szent-Györgyi had begun
to investigate respiration in muscle tissue, using minced
pigeon breast muscle. Pigeon breast was an ideal material,
a powerful muscle that burned energy at a high rate to
sustain flight, and also readily available. It was already
known that fumaric, malic, and succinic acids (collectively
called dicarboxylic acids) played some role in respiration,
but scientists assumed that they were consumed in the
process. When Szent-Györgyi added small amounts of these to
his minced pigeon muscle, he found that far more oxygen was
consumed than would be needed to oxidize them. The acids
were not consumed as fuels, he realized, but served as
catalysts, i.e., they maintained the combustion reaction
without being changed themselves. Each of them stimulated
the oxidation of a carbohydrate present in the tissue
cells. This was an important new idea. Szent-Györgyi
proposed that the hydrogen from a substance in the cell
(e.g., a carbohydrate) reduced a first dicarboxylic acid,
the oxaloacetic acid; the resulting malic acid reduced
fumaric acid; the succinic acid thus produced in turn
transferred its hydrogen to cytochromes. By 1937,
Szent-Györgyi had identified the process as a cycle and was close
to elaborating all of the steps that generate adenosine
triphosphate (ATP), the energy-carrying molecule in all
living cells. As it turned out, Szent-Györgyi's focus on
malate and oxaloacetate was an error, and Hans Krebs soon
found that the key link was citric acid. Thus
"Szent-Györgyi's cycle" became the citric acid cycle or Krebs
cycle; Krebs, who won a Nobel prize in 1953 for the work,
later called it the tricarboxylic acid cycle.

Szent-Györgyi was quite surprised when, in October 1937, he
was informed by the Royal Karolinska Institute in Stockholm
that he had been awarded the Nobel Prize for Physiology or
Medicine, "for his discoveries in connection with the
biological combustion processes, with especial reference to
vitamin C and the catalysis of fumaric acid." (Norman
Haworth and another vitamin researcher Paul Karrer, shared
that year's prize in chemistry, also in part for work on
vitamin C.) The Nobel prize made Szent-Györgyi a national
hero in Hungary; he was only the fourth Hungarian Nobel
laureate, and the first to win it while actually residing
there.

Szent-Györgyi's research into muscle tissue respiration led
him to the question of how muscle moves. Russian
researchers had reported in 1939 that the muscle protein
myosin could interact with and split ATP. Though discovered
in 1929, ATP had not yet been identified as the principal
source of energy in cells (it releases tremendous energy
when its phosphate bonds are split). Szent-Györgyi reasoned
that the myosin-ATP interaction might well explain the
movement of muscle. To learn more about how muscle tissue
changes its shape and size, and about the chemical
substances involved, he extracted myosin from rabbit
muscle, drew it into a hypodermic syringe, then pressed it
out into fine threads. When he added ATP, the threads
rapidly contracted to one-third their original size, just
like a muscle fiber tensing. "To see myosin contract and
see one of the oldest and most mysterious signs of
life--motion--reproduced the first time in vitro. . . was the
most
exciting experience of my research career," he commented
later. He and his research team, notably Bruno Straub and
Ilona Banga, went on to discover that muscle tissue
contained a second protein, actin, which combined with
myosin to form interlocking fibers; the higher the
percentage of actin, the stronger the fiber's contraction
response to ATP. By 1944, the team had elucidated the
mechanism of muscle contraction and clarified the role of
ATP in the process. They published a series of papers,
Studies on Muscle from the Institute of Medical
Chemistry
which reported on their five years of research.

In 1944, however, Szent-Györgyi had more serious problems.
Never a supporter of fascist policies, he had helped Jewish
colleagues (including Hans Krebs) during the 1930s, and had
strongly resisted the growing campus anti-Semitism and
militancy, even facing down angry groups of students at
times. Hungary was loosely allied with the Axis powers
after 1938, but by 1942 many intellectuals (including
Szent-Györgyi) and some politicians were publicly
protesting this alliance and working quietly to undermine
the Nazis. In 1943 the Hungarian prime minister asked
Szent-Györgyi to open secret negotiations with the Allies.
Szent-Györgyi traveled to Istanbul (allegedly to give a
scientific lecture) and made contact with Allied agents
there, but German agents learned of the plan. By the summer
of 1944, at Hitler's request, Szent-Györgyi was under house
arrest. He slipped away after several months, and spent the
remainder of the war hiding from the Nazis in Szeged and
Budapest.